The proposed research will be concerned with the relationships between diabetes, arterial metabolism and atherogenesis. The studies will utilize unique animal models with naturally occurring diabetes to study the structure and function of arteries during different stages of diabetes, during dietary induction and regression of atheromatous lesions, and following insulin therapy. Arterial glucose utilization, lipid synthesis, and the polyol pathway will be examined in isolated arterial segments from these animals. Electron microscopic study of arteries from prediabetic and diabetic animals will be performed. Cell suspensions and subcellular systems for studying arterial metabolism will be developed, and various aspects of the in vitro metabolism of carbohydrates and lipids will be studied in human and animal arteries. Hypercholesterolemia in diabetic animals will be examined with respect to its relationship to inheritance, severity of diabetes, diet, and vascular lesions. In addition, the body metabolism of cholesterol will be studied in diabetic man and animals using isotope kinetic and sterol balance techniques, and the influence of insulin therapy will be assessed.